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C-Jun the Activator Protein 1 Transcription Factor T Cell Regulation of αβ/ δγ T Cell Development by the Activator Protein 1 Transcription Factor c-Jun This information is current as Lluís Riera-Sans and Axel Behrens of September 28, 2021. J Immunol 2007; 178:5690-5700; ; doi: 10.4049/jimmunol.178.9.5690 http://www.jimmunol.org/content/178/9/5690 Downloaded from References This article cites 61 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/178/9/5690.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 28, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2007 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Regulation of ␣␤/␥␦ T Cell Development by the Activator Protein 1 Transcription Factor c-Jun1 Lluı´s Riera-Sans2 and Axel Behrens3 c-Jun is a member of the AP-1 family of transcription factors, the activity of which is strongly augmented by TCR signaling. To elucidate the functions of c-Jun in mouse thymic lymphopoiesis, we conditionally inactivated c-Jun specifically during early T cell development. The loss of c-Jun resulted in enhanced generation of ␥␦ T cells, whereas ␣␤ T cell development was partially arrested at the double-negative 3 stage. The increased generation of ␥␦ T cells by loss of c-Jun was cell autonomous, because in a competitive reconstitution experiment the knockout-derived cells produced more ␥␦ T cells than did the control cells. C-jun- deficient immature T cells failed to efficiently repress transcription of IL-7R␣, resulting in augmented IL-7R␣ mRNA and surface levels. Chromatin immunoprecipitation assays revealed binding of c-Jun to AP-1 binding sites present in the IL-7R␣ promoter, ␣ ␣␤ ␥␦ indicating direct transcriptional regulation. Thus, c-Jun controls the transcription of IL-7R and is a novel regulator of the / Downloaded from T cell development. The Journal of Immunology, 2007, 178: 5690–5700. ature T lymphocytes derive from lymphoid precursors not be the sole determinant of linage decision. If expression of an through several distinct cell fate specification events in-frame ␥␦ TCR invariably led to ␥␦ T cell development, one M (1). Common lymphoid precursors, which have al- might expect a complete block in ␣␤ T cell development in mice ready lost erythroid and myeloid potential, separate into B and T expressing a rearranged ␥␦ TCR transgene. This, however, is not http://www.jimmunol.org/ cell precursors in the thymus. Immature pro-T cells then develop the case: many ␥␦ TCR-transgenic mice contain significant into mature T cells characterized by surface expression of either numbers of ␣␤ lineage T cells (4, 5). Conversely, significant the CD4ϩ or the CD8ϩ coreceptor before leaving the thymus. numbers of ␥␦ T cells are present in mice expressing a rear- Thymocytes can be divided into four major subsets based on the ranged ␣␤ TCR transgene (6). Recent work suggests that quan- Ϫ Ϫ expression of CD4 and CD8. The CD4 CD8 double-negative titative differences in TCR signaling appear to be influencing (DN)4 cells are the most immature subset. The DN population can ␣␤/␥␦ lineage commitment (7, 8). be further divided into four subsets (DN1–DN4) based on their To make the developmental transition from DN3 to DN4, the differential expression of CD44 and CD25. DN thymocytes mature TCR chains must be assembled into the pre-TCR complex, which ϩ Ϫ ϩ ϩ in the order of CD44 CD25 (DN1), CD44 CD25 (DN2), consists of a TCR ␤-chain, the invariant pT ␣-chain, and CD3 by guest on September 28, 2021 Ϫ ϩ Ϫ Ϫ CD44 CD25 (DN3), and CD44 CD25 (DN4) (2). components. Only cells that have a functional pre-TCR survive the The decision between ␣␤ and ␥␦ T cells occurs at the DN stage, transition from DN3 to DN4, a process also known as ␤ selection. but the exact time point of specification remains to be determined In mice deficient for components of the pre-TCR developing ␣␤ (3). Likewise, whether the signaling from the ␣␤ or the ␥␦ TCR, lineage thymocytes are blocked at the DN3 stage and do not sur- respectively, is the instructive determinant of lineage choice or vive (9–14). The requirement for some pre-TCR components is whether ␣␤/␥␦ commitment occurs at least in part independently confined to developing ␣␤ T cells, because the absence of CD3␦ of TCR rearrangement is unclear. and CD3␨ has no effect on and pT␣ deficiency even increases ␥␦ Although it appears that TCR gene rearrangements influence the T cell number (9, 14, 15). ␣␤ vs ␥␦ lineage decision, there are also indications that this can- A number of signaling pathways in addition to the pre-TCR have been implicated in ␣␤/␥␦ lineage commitment, one of which is the IL-7/IL-7R pathway. IL-7R signaling is essential for the Mammalian Genetics Laboratory, Lincoln’s Inn Fields Laboratories, London Re- generation and maintenance of precursor cells committed to either search Institute, Cancer Research, London, United Kingdom the T or B cell lineage. In early thymocyte development, the loss Received for publication March 9, 2006. Accepted for publication February 22, 2007. of IL-7 or IL-7R␣ results in a substantial reduction in the number The costs of publication of this article were defrayed in part by the payment of page of total thymocytes and mature T cells (16, 17). IL-7R signaling charges. This article must therefore be hereby marked advertisement in accordance has an especially drastic effect on ␥␦ T cells, which are absent in with 18 U.S.C. Section 1734 solely to indicate this fact. mice lacking IL-7 or IL-7R␣ (18, 19). IL-7 treatment augments ␥␦ 1 The London Research Institute is funded by Cancer Research U.K. L.R.-S. acknowl- edges support from an European Union Marie-Curie fellowship. T cell number in ex vivo systems (20, 21), suggesting that IL-7 ␥␦ 2 Current address: Epithelial Homeostasis and Cancer, Department of Cell Differen- signaling can promote T cell development. tiation and Cancer, Center of Genomic Regulation, Doctor Aiguader 88, 08003 Bar- The transcription factor AP-1 consists of a variety of dimers celona, Spain. composed of members of the Fos and Jun families of proteins (22). 3 Address correspondence and reprint requests to Dr. Axel Behrens, Cancer Research Although the Fos proteins (c-Fos, FosB, Fra-1, Fra-2) can only U.K. London Research Institute, Lincoln’s Inn Fields Laboratories, Mammalian Genetics Laboratory, 44, Lincoln’s Inn Fields, London WC2A 3PX, U.K. E-mail heterodimerize with members of the Jun family, the Jun proteins address: [email protected] (c-Jun, JunB, JunD) can both homodimerize and heterodimerize 4 Abbreviations used in this paper: DN, double negative; BM, bone marrow; DAPI, with other Jun or Fos members to form transcriptionally active 4Ј,6Ј-diamidino-2-phenylindole; ChIP, chromatin immunoprecipitation; FTOC, fetal complexes (22–24). thymus organ culture. The activity of the AP-1 transcription factor is strongly induced Copyright © 2007 by The American Association of Immunologists, Inc. 0022-1767/07/$2.00 in response to numerous extracellular stimuli including TCR www.jimmunol.org The Journal of Immunology 5691 signaling. AP-1 stimulation is mediated, in part, by the phosphor- ylation of c-Jun by the JNKs (25). c-Jun N-terminal phosphoryla- tion at serine residues 63 and 73 and threonine residues 91 and 93 within its transactivation domain is thought to increase transcrip- tion of target genes, one of which is the c-jun gene itself (26). The function of JNK signaling in T cells has been extensively studied and has revealed a multitude of JNK functions ranging from T cell development and proliferation to T cell differentiation (27–31). c-Jun is one of the main targets of JNK signaling, but its function in T cells is less well understood, in part due to the em- bryonic lethality of c-jun-deficient mice (32, 33). RAG2 comple- mentation experiments with c-junϪ/Ϫ ES cells revealed reduced restoration of thymocytes but normal T cell proliferation and IL-2 production (34). The role of c-Jun and AP-1 in thymopoiesis has also been in- vestigated using dominant-negative approaches in transgenic mice. B cell-activating transcription factor belongs to the AP-1 super- family of basic leucine zipper transcription factors and forms het- erodimers with Jun that possess minimal transcriptional activity. Downloaded from Overexpression of B cell-activating transcription factor using the lck promoter resulted in a specific defect in NKT cell development, and reduced thymocyte proliferation (35, 36). Moreover, trans- genic overexpression of a dominant-negative version of c-Jun caused aberrant thymic organization accompanied by reduced T cell proliferation and IL-2 production (37). T cell development has http://www.jimmunol.org/ also been investigated in junAA mice, in which serines 63 and 73 in the c-Jun N terminus were replaced by alanines using a knock-in approach, but no defects were found (38, 39). To clarify the role of c-Jun in T cell development, we have used conditional mutagenesis to generate mice lacking c-Jun in the T cell lineage (c-jun⌬T mice; Refs.
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